understanding of product & process for installation of appropriate controls (12 april 2017)

Understanding of Product & Process

For Installation of Appropriate Controls

Roohi B. Obaid, R. Ph.Civil Services Officer

Member ISPE & PDA

12 April 2017

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Not the view of DRAP

Current judgment

No obligation on DRAP

Regulatory experience

This presentation discusses science and has nothing to do with

any commercial Product.

Why How

Why Howe.g. Saxagliptin

Lets have a look & walk through real cases

05 Feb 2017

Bupripion HCl ER

2.7 lakh bottle

Dissolution failure

At 18 month of

stability

Does anybody want to see such news early morning?

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Don’t assume but

keep respecting

science

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Don’t assume but

keep respecting

science

Understand your

product &

process

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Don’t assume but

keep respecting

science

Understand your

product &

process

Before it

happens

Drug assay is

compliant

Drug assay is

compliant

Drug is not available

for absorption

Drug assay is

compliant

Drug is not available

for absorption

Do you expect

effect?

Therapeutic

effect under

question

Therapeutic

effect under

questionDisease may progress

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Pain killers

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Pain killers Cardiac drug

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Pain killers Cardiac drug Anti epileptic drug

2013

Amidate Injection

(Etomidate)

Degradation during

stability

Hospira & Pfizer product

Top Reasons for Recalls

1

Super or sub potent formulations

Digoxin (double

thickness)

Actavis 2008

1

Super or sub potent formulations

Digoxin (double

thickness)

Actavis 2008Poor Manufacturing Control

1

Super or sub potent formulations

Morphine (double size)

KV Pharmaceuticals 2008

Company closed because

they knew the problem &

failed to inform FDA

Fine of 27.6 million USD

1

Super or sub potent formulations

Morphine (double size)

KV Pharmaceuticals 2008

Company closed because

they knew the problem &

failed to inform FDA

Fine of 27.6 million USD

Poor Manufacturing Control

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

Wrong sort of container used

to store highly acidic or

basic solution

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

Glass, silicon & stainless steel …. …in the

glass used to manufacture vials and other

containers.

wear and tear of machinery, abrasion of

stoppers and plungers …in the glass used to

manufacture vials and other containers.

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

Inadequate understanding of

the product and process

3

API’s Contamination

Bulk heparin in China

Over sulfated Chondroitin

Sulfate

80 deaths in USA alone

Found deliberated &

economically motivated

3

API’s Contamination

Bulk heparin in China

Over sulfated Chondroitin

Sulfate

80 deaths in USA alone

Found deliberated &

economically motivated

Weak supply chain

Unknown contaminant later

named OSCS

3

API’s Contamination

GSK Worthing UK facility

July 2015

Bactobran cream

containing Mupirocin

recalled

3

API’s Contamination

GSK Worthing UK facility

July 2015

Bactobran cream

containing Mupirocin

recalled

API Mupirocin

contaminated with penicillin &

foreign substances during Mfg

process

3

API’s Contamination

GSK Worthing UK facility

July 2015

Bactobran cream

containing Mupirocin

recalled

Inadequate Controls to

Prevent contamination

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

Inappropriate practice during operations

Personnel & material movement, use of

non-dedicated facilities

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

Cleaning is not

a substitute for

segregation

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

Cleaning is not

a substitute for

segregation

No safe level of

penicillin

contamination has

been determined to

be a tolerable risk

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

Loose ink in blister packaging line

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

Loose ink in blister packaging line

Diethylphthalate (DEP) … from

desiccant cartridge

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

Loose ink in blister packaging line

Diethylphthalate (DEP) … from

desiccant cartridge

Cause could not be assigned

whether a residue from API or

improper packaging ….

4

Sterility Failure

Various drugs for potential

sterility failure found

contaminated with

pathogenic organisms

High threat for HIV, Cystic

Fibrosis or TB

4

Sterility Failure

Various drugs for potential

sterility failure found

contaminated with

pathogenic organisms

High threat for HIV, Cystic

Fibrosis or TB

Poor manufacturing & environmental

control

5

Contamination with TBA

Bad odour in product

J&J 2009

Pfizer 2010

TBP, a wood preservative

for pallets converted to

TBA giving bad odour

5

Contamination with TBA

Bad odour in product

J&J 2009

Pfizer 2010

TBP, a wood preservative

for pallets converted to

TBA giving bad odour

Poor control and desensitized alarms,

throwing away of wake up calls, ended

up with largest recall

6

Disintegration Failure

Soft gel capsule failed in

disintegration

Millions of capsules

recalled

Company shut down for

a long time

6

Disintegration Failure

Soft gel capsule failed in

disintegration

Millions of capsules

recalled

Company shut down for

a long time

6

Dissolution failure

100’s of batches of

Paracetamol tablet

failed in Dissolution

6

Dissolution failure

100’s of batches of

Paracetamol tablet

failed in Dissolution

7

Manufacturing with poor knowledge

Rivaroxaban Tablet

Failure in CDP

7

Manufacturing with poor knowledge

Rivaroxaban Tablet

Failure in CDP

7

Manufacturing with poor knowledge

Ramipril tablets

Process degradation

found

7

Manufacturing with poor knowledge

Ramipril tablets

Process degradation

found

Able Laboratories, NJ

A story of Generic Manufacturing Company’s

Collapse

1999 to 2005

Enormous growth & expansion

17 - 55% per share

1999 to 2005

Enormous growth & expansion

17 - 55% per share

2005 - Major recall due to falsification of data

Flouting, altering or manipulation & reporting

1999 to 2005

Enormous growth & expansion

17 - 55% per share

2005 - Major recall due to falsification of data

Flouting, altering or manipulation & reporting

2007 - Charged

All drugs withdrawn, company shut down

Lets hear and watch the way Leaders

come forward to protect trust

These are the norms of moral business

Closing Words

Audit communicate &

monitor your suppliers

Understand CQA of your product

Understand CPP of your process

Validate your process

Closing Words

Develop a Control Strategy

Maintain your

equipments & facility

Trend and monitor all

the components

Modify the Control

Strategy if required

Maintain the state of control

Safe, efficacious

& have correct identity

Deliver the same

performance as claimed

Perform consistently over shelf

life

Made in a manner that

ensure quality

Will be available

when needed